Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1617—Organic compounds, e.g. phospholipids, fats
  • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
  • A61K9/2806—Coating materials
  • A61K9/2833—Organic macromolecular compounds
  • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
  • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/4816—Wall or shell material
  • A61K9/4825—Proteins, e.g. gelatin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/4841—Filling excipients; Inactive ingredients
  • A61K9/4858—Organic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/4841—Filling excipients; Inactive ingredients
  • A61K9/4875—Compounds of unknown constitution, e.g. material from plants or animals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
  • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
  • A61K9/2806—Coating materials
  • A61K9/2833—Organic macromolecular compounds
  • A61K9/2853—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers, poly(lactide-co-glycolide)

Definitions

• the present invention is concerned with novel pyrido[2,l-a]isoquinoline derivatives, their manufacture and their use as medicaments.
• R 5 and R together with the nitrogen atom to which they are attached form a 4-, 5-, 6- or 7-membered saturated or unsaturated heterocyclic ring optionally containing a further heteroatom selected from nitrogen, oxygen and sulfur, said heterocyclic ring being optionally mono-, di-, or tri-substituted, independently, with lower alkyl, halogenated lower alkyl, oxo, dioxo and/or cyano; and pharmaceutically acceptable salts thereof.
• the enzyme dipeptidyl peptidase IN (EC.3.4.14.5, abbreviated in the following as DPP-IV) is involved in the regulation of the activities of several hormones.
• DPP-IV is degrading efficiently and rapidly glucagon like peptide 1 (GLP-1), which is one of the most potent stimulator of insulin production and secretion.
• GLP-1 glucagon like peptide 1
• Inhibiting DPP-IV would potentiate the effect of endogenous GLP-1, and lead to higher plasma insulin concentrations.
• higher plasma insulin concentration would moderate the dangerous hyperglycaemia and accordingly reduce the risk of tissue damage.
• the compounds of the present invention are useful for the treatment and/or prophylaxis of diabetes, particularly non-insulin dependent diabetes mellitus, and/or impaired glucose tolerance, as well as other conditions wherein the amplification of action of a peptide normally inactivated by DPP-IV gives a therapeutic benefit.
• the compounds of the present invention can also be used in the treatment and/or prophylaxis of obesity, inflammatory bowel disease, Colitis Ulcerosa, Morbus Crohn, and/or metabolic syndrome or ⁇ -cell protection.
• the compounds of the present invention can be used as diuretic agents and for the treatment and/or prophylaxis of hypertension.
• the compounds of the present invention exhibit improved therapeutic and pharmacological properties compared to other DPP-IV inhibitors known in the art, such as e.g. in context with pharmacokinetics and bioavailability.
• a 4-, 5-, 6- or 7-membered saturated or unsaturated heterocyclic ring optionally containing a further heteroatom selected from nitrogen, oxygen and sulfur refers to a non-aromatic heterocyclic ring, said heterocyclic ring being optionally mono-, di-, or tri-substituted, independently, with lower alkyl, halogenated lower alkyl, oxo, dioxo and/or cyano.
• Such saturated heterocyclic rings are for example pyrrolidinyl, piperidinyl, azepanyl, [l,2]thiazinanyl, [l,3]oxazinanyl, oxazolidinyl, thiazolidinyl or azetidinyl.
• unsaturated heterocyclic rings are 5,6-dihydro-lH-pyridin- 2-one, pyrrolinyl, tetrahydropyridine or dihydropyridine.
• residue R 3 is lower alkoxy, with methoxy, ethoxy, propoxy, n-butoxy and isobutoxy being preferred, or hydrogen or hydroxy. Most preferable residue R 3 is methoxy or hydroxy, with methoxy being especially preferred.
• residue R 4 is lower alkoxy, preferably methoxy, hydrogen or hydroxy. Most preferable residue R 4 is hydrogen.
• R 6 is lower alkylsulfonyl, preferably ethylsulfonyl, or lower alkylcarbonyl, preferably ethylcarbonyl, or cycloalkylcarbonyl, preferably cyclopropylcarbonyl.
• R 5 and R 6 together with the nitrogen atom to which they are attached form a 4-, 5-, 6- or 7-membered saturated or unsaturated heterocyclic ring optionally containing a sulfur atom or an oxygen atom as a further heteroatom in the ring, said heterocyclic ring being optionally mono- or di-substituted, independently, with lower alkyl such as methyl or ethyl, halogenated lower alkyl such as fluoromethyl, oxo, dioxo and/or cyano.
• lower alkyl such as methyl or ethyl
• halogenated lower alkyl such as fluoromethyl, oxo, dioxo and/or cyano.
• Preferred compounds of general formula (I) are those selected from the group consisting of: (RS,RS,RS)-(2-amino-9,10-dimethoxy-l,3,4,6,7,llb-hexahydro-2H-pyrido[2,l- a] isoquinolin-3 -yl) -pyrrolidin- 1 -yl-methanone, (RS,RS,RS)-(2-amino-9,10-dimethoxy-l,3,4,6,7,llb-hexahydro-2H-pyrido[2,l- a]isoquinoKn-3-yl)-thiazolidin-3-yl-methanone, (RS,RS,RS)-(2-amino-9,10-dimethoxy-l,3,4,6,7,llb-hexahydro-2H-pyrido[2,l- a]isoquinolin-3-yl)-azetidin-l-yl-methanone, (SS)-
• the amino protecting group is cleaved by catalytic hydrogenation under conditions well-known to the skilled person.
• Compounds of formula B are well known in the art (e.g., Helv. Chim. Ada 1958, 41, 119).
• Reaction of B with ammonium acetate in a solvent such as methanol produces the ⁇ -enamino-ester C, which is reduced, preferably with sodium borohydride/trifluoroacetic acid, to the corresponding the ⁇ -amino-ester.
• the amino group is optionally benzylated and then converted to the tert-butyl carbamate of formula D.
• the ester group of D is hydrolyzed using a base, preferably potassium hydroxide or sodium hydroxide in a water/tetrahydrofuran mixture, to yield the acid E.
• Compound E is reacted with an appropriate amine in the presence of a suitable coupling agent, e. g., O-(7-azobenzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (HATU), and abase, e. g., N-ethyldiisopropylamine, to yield amide A2.
• a suitable coupling agent e. g., O-(7-azobenzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (HATU)
• abase
• Example lc The title compound was produced in accordance with the general method of Example Id from (RS,RS,RS)-2-tert-butoxycarbonylamino-9,10-dimethoxy-l,3,4,6,7,llb-hexahydro- 2H-pyrido[2,l-a]isoquinoline-3-carboxylic acid (Example lc) and thiazolidine.
• Example le fiOm (RS,RS,RS)-[3-(azetidine-l-carbonyl)-9,10-dimethoxy-l,3,4,6,7,llb-hexahydro- 2H-pyrido[2,l-a]isoquinolin-2-yl]-carbamic acid tert-butyl ester.
• White foam MS (ISP) 346.2 (M+H) + .
• Example 5c The title compound was produced in accordance with the general method of Example 5c from (RS,RS,RS)-(3-amino-9,10-dimethoxy-l,3,4,6,7,llb-hexahydro-2H-pyrido[2,l- a]isoquinolin-2-yl)-carbamic acid tert-butyl ester (Example 5b) and 5-chloro-3- methylvaleryl chloride (DE2621576).
• Example 5d The title compound was produced in accordance with the general method of Example 5d from (RS,RS,RS)-[3-(4-chloro-butyrylamino)-9,10-dimethoxy-l,3,4,6,7,llb-hexahydro- 2H-pyrido[2,l-a]isoquinolin-2-yl] -carbamic acid tert-butyl ester. Light yellow solid, MS (ISP) 446.3 (M+H) + .
• Example 5c The title compound was produced in accordance with the general method of Example 5c from (RS,RS,RS)-(3-amino-9,10-dimethoxy-l,3,4,6,7,llb-hexahydro-2H-pyrido[2,l- a] isoquinolin-2-yl) -carbamic acid tert-butyl ester (Example 5b) and 4-chloro-3- methylbutyryl chloride (Chem. Ber. 1964, 97, 2544). White solid, MS (ISP) 496.3 (M+H) + .
• the tide compound was produced in accordance with the general method of Example 5d from (RS,RS,RS)-[3-(3-chloro-propane-l-sulfonylamino)-9,10-dimethoxy-l,3,4,6,7,llb- hexahydro-2H-pyrido[2,l-a]isoquinolin-2-yl] -carbamic acid tert-butyl ester.
• MS (ISP) 482.3 (M+H) + MS (ISP) 482.3 (M+H) + .
• Example 5c The title compound was produced in accordance with the general method of Example 5c from (RS,RS,RS)-(3-amino-9,10-dimethoxy-l,3,4,6,7,llb-hexahydro-2H-pyrido[2,l- a]isoquinolin-2-yl)-carbamic acid tert-butyl ester (Example 5b) and 4- chlorobutanesulfonyl chloride (DE1300933).
• MS (ISP) 532.3 (M+H) + MS (ISP) 532.3 (M+H) + .
• the tide compound was produced from (S)-(6,7-dimethoxy-l,2,3,4-tetrahydro- isoquinolin-1-yl) -acetic acid ethyl ester, in accordance with the synthesis of the racemate, (RS,RS,RS)-(3-amino-9,10-dimethoxy-l,3,4,6,7,llb-hexahydro-2H- ⁇ yrido[2,l- a]isoquinolin-2-yl)-carbamic tert-butyl ester (Example 5b).
• t 19.3 min
• tide compounds were produced in accordance with the general method of Examples 6 and 7 from (RS,RS,RS,RS)-l-(2-amino-9,10-dimethoxy-l,3,4,6,7,llb-hexahydro-2H- pyrido [2, 1 -a] isoquinolin-3-yl)-4-methyl-pyrrolidin-2-one (Example 18).
• Example 5c The title compound was produced in accordance with the general method of Example 5c from (RS,RS,RS)-(3-amino-9,10-dimethoxy-l,3,4,6,7,llb-hexahydro-2H-pyrido[2,l- a]isoquinolin-2-yl)-carbamic acid tert-butyl ester (Example 5b) and 3-chloromethyl-4- fluoro-butyryl chloride.
• the tide compound was produced in accordance with the general method of Example 5d from (RS,RS,RS)-[3-(5-chloro-4-methyl-pentanoylamino)-9,10-dimethoxy- l,3,4,6,7,llb-hexahydro-2H-pyrido[2,l-a]isoquinolin-2-yl]-carbamic acid tert-butyl ester.
• the tide compound was produced in accordance with the general method of Example le from (RS,RS,RS)-[9,10-dimethoxy-3-(5-methyl-2-oxo- ⁇ iperidin-l-yl)-l,3,4,6,7,llb- hexahydro-2H-pyrido[2,l-a]isoquinolin-2-yl]-carbamic acid tert-butyl ester.
• the tide compound was produced in accordance with the general method of Example 5c from (RS,RS,RS)-(3-amino-9,10-dimethoxy- 1,3,4,6,7,1 lb-hexahydro-2H-pyrido [2,1- a]isoquinolin-2-yl) -carbamic acid tert-butyl ester (Example 5b) and propionyl chloride.
• the tide compound was produced in accordance with the general methods of Example 5c and le from (RS,RS,RS)-(3-amino-9,10-dimethoxy-l,3,4,6,7,llb-hexahydro-2H- pyrido[2,l-a]isoquinolin-2-yl)-carbamic acid tert-butyl ester (Example 5b) and cyclopropanecarbonyl chloride. Off-white solid, MS (ISP) 346.3 (M+H) + .
• the tide compound was produced in accordance with the general method of Example 5c from (S,S,S)-(3-amino-9,10-dimethoxy-l,3,4,6,7,llb-hexahydro-2H-pyrido[2,l- a]isoquinolin-2-yl) -carbamic acid tert-butyl ester (Example 16b) and 3-chloromethyl-4- fluoro-butyryl chloride (Example 23b). Off-white solid.
• Example 30c The tide compound was produced in accordance with the general method of Example 30c from [(S,S,S)-3-((R)-4-fluoromethyl-2-oxo-pyrrolidin-l-yl)-9,10-dimethoxy- l,3,4,6,7,llb-hexahydro-2H-pyrido[2,l-a]isoquinolin-2-yl] -carbamic acid tert-butyl ester (Example 30b).
• Example 5c The title compound was produced in accordance with the general methods of Example 5c, 5d, and le from (RS,RS,RS)-(3-amino-9,10-dimethoxy-l,3,4,6,7,llb-hexahydro-2H- pyrido[2,l-a]isoquinolin-2-yl)-carbamic acid tert-butyl ester (Example 5b) and 2- chloroethyl chloroformate. Light yellow solid, MS (ISP) 348.5 (M+H) + .
• the tide compound was produced in accordance with the general method of Example 23b from ⁇ -valerolactone. Colourless liquid, 1H-NMR (300 MHz, CDC1 3 ): 4.10-4.00 (m, 1 H), 3.25-3.05 (m, 2 H), 2.25-2.15 (m, 1 H), 2.05-1.95 (m, 1 H), 1.55 (d, 3 H).
• the tide compound was produced in accordance with the general method of Example 5c from (RS,RS,RS)-(3-amino-9,10-dimethoxy-l,3,4,6,7,llb-hexahydro-2H- ⁇ yrido[2,l- a] isoquinolin-2-yl) -carbamic acid tert-butyl ester (Example 5b) and 4-chloro-pentanoyl chloride. Off-white solid, MS (ISP) 496.4 (M+H) + .
• the tide compound was produced in accordance with the general methods of Example 5d and le from [(RS,RS,RS)-3-(4-chloro-pentanoylamino)-9,10-dimethoxy- l,3,4,6,7,llb-hexahydro-2H-pyrido[2,l-a]isoquinolin-2-yl]-carbamic acid tert-butyl ester. Yellow solid, MS (ISP) 360.1 (M+H) + .
• the tide compound was produced in accordance with the general method of Example 5d from [(RS,RS,RS)-3-(2-cUoro-l-fluoromeli yl-ethoxycarbonylammo)-9,10-dimethoxy- 1,3,4,6,7,1 lb-hexahydro-2H-pyrido[2,l-a]isoquinolin-2-yl] -carbamic acid tert-butyl ester.
• the tide compound was produced in accordance with the general method of Example 23b from ⁇ -valerolactone. Colourless liquid, 1H-NMR (300 MHz, CDC1 3 ): 3.61 (t, 2 H), 3.25-3.15 (m, 1 H), 2.40-2.25 (m, 1 H), 2.00-1.85 (m, 1 H), 1.36 (d, 3 H).
• Example 35a The title compound was produced in accordance with the general method of Example 35a from (RS,RS,RS)-(3-amino-9,10-dimethoxy-l,3,4,6,7,llb-hexahydro-2H- pyrido[2,l-a]isoquinolin-2-yl)-carbamic acid tert-butyl ester (Example 5b) and 1- chloro-propan-2-ol (/. Chem. Soc. Perkin Trans. 1 1983, 3019). Off-white solid, MS (ISP) 498.4 (M+H) + .
• Film coated tablets containing the following ingredients can be manufactured in a conventional manner:
• Kernel Compound of formula (I) 10.0 mg 200.0 mg Microcrystalline cellulose 23.5 mg 43.5 mg Lactose hydrous 60.0 mg 70.0 mg Povidone K30 12.5 mg 15.0 mg Sodium starch glycolate 12.5 mg 17.0 mg Magnesium stearate 1.5 mg 4.5 mg (Kernel Weight) 120.0 mg 350.0 mg
• the active ingredient is sieved and mixed with microcrystalline cellulose and the mixture is granulated with a solution of polyvinylpyrrolidone in water.
• the granulate is mixed with sodium starch glycolate and magnesium stearate and compressed to yield kernels of 120 or 350 mg respectively.
• the kernels are lacquered with an aq. solution / suspension of the above mentioned film coat.
• Capsules containing the following ingredients can be manufactured in a conventional manner:
• the components are sieved and mixed and filled into capsules of size 2.

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Organic Chemistry (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Epidemiology (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Diabetes (AREA)
• Hematology (AREA)
• Obesity (AREA)
• Endocrinology (AREA)
• Botany (AREA)
• Zoology (AREA)
• Molecular Biology (AREA)
• Biophysics (AREA)
• Dermatology (AREA)
• Cardiology (AREA)
• Child & Adolescent Psychology (AREA)
• Urology & Nephrology (AREA)
• Emergency Medicine (AREA)
• Heart & Thoracic Surgery (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Priority Applications (20)

Applications Claiming Priority (2)

Publications (1)

Family

ID=33515111

Family Applications (1)

Country Status (35)

Cited By (69)

Families Citing this family (19)

Citations (10)

Family Cites Families (10)

• 2004
  • 2004-06-11 PT PT04739841T patent/PT1638970E/pt unknown
  • 2004-06-11 AT AT04739841T patent/ATE489387T1/de active
  • 2004-06-11 NZ NZ544221A patent/NZ544221A/en not_active IP Right Cessation
  • 2004-06-11 ES ES04739841T patent/ES2355105T3/es active Active
  • 2004-06-11 DK DK04739841.7T patent/DK1638970T3/da active
  • 2004-06-11 WO PCT/EP2004/006355 patent/WO2005000848A1/en active Application Filing
  • 2004-06-11 BR BRPI0411713A patent/BRPI0411713B8/pt not_active IP Right Cessation
  • 2004-06-11 MX MXPA05013904A patent/MXPA05013904A/es active IP Right Grant
  • 2004-06-11 KR KR1020057024424A patent/KR100730867B1/ko active IP Right Grant
  • 2004-06-11 CA CA2529443A patent/CA2529443C/en not_active Expired - Fee Related
  • 2004-06-11 RS YU20050939A patent/RS52397B/sr unknown
  • 2004-06-11 CN CNB200480017358XA patent/CN100374439C/zh not_active Expired - Fee Related
  • 2004-06-11 EP EP04739841A patent/EP1638970B1/en active Active
  • 2004-06-11 EA EA200501936A patent/EA009591B1/ru not_active IP Right Cessation
  • 2004-06-11 AU AU2004251830A patent/AU2004251830B8/en not_active Ceased
  • 2004-06-11 PL PL04739841T patent/PL1638970T3/pl unknown
  • 2004-06-11 DE DE602004030244T patent/DE602004030244D1/de active Active
  • 2004-06-11 JP JP2006515913A patent/JP4160616B2/ja not_active Expired - Fee Related
  • 2004-06-11 SI SI200431593T patent/SI1638970T1/sl unknown
  • 2004-06-16 TW TW093117363A patent/TWI297011B/zh not_active IP Right Cessation
  • 2004-06-17 AR ARP040102105A patent/AR044795A1/es active IP Right Grant
  • 2004-06-17 US US10/870,580 patent/US7122555B2/en active Active
  • 2004-06-18 MY MYPI20042371A patent/MY140039A/en unknown
  • 2004-11-06 UA UAA200600527A patent/UA82242C2/uk unknown
• 2005
  • 2005-12-12 NO NO20055887A patent/NO332126B1/no not_active IP Right Cessation
  • 2005-12-13 CR CR8147A patent/CR8147A/es unknown
  • 2005-12-15 IL IL172618A patent/IL172618A/en active IP Right Grant
  • 2005-12-15 MA MA28665A patent/MA27883A1/fr unknown
  • 2005-12-16 TN TNP2005000320A patent/TNSN05320A1/en unknown
  • 2005-12-19 ZA ZA200510298A patent/ZA200510298B/en unknown
  • 2005-12-20 CO CO05128097A patent/CO5640155A2/es active IP Right Grant
  • 2005-12-20 EC EC2005006240A patent/ECSP056240A/es unknown
• 2007
  • 2007-01-10 HK HK07100369A patent/HK1093503A1/xx not_active IP Right Cessation
• 2011
  • 2011-01-12 HR HR20110018T patent/HRP20110018T1/hr unknown
  • 2011-01-27 CY CY20111100091T patent/CY1111425T1/el unknown

Patent Citations (10)

Also Published As

Similar Documents

Legal Events